U.S. Pat. Nos. 5,532,415, 5,387,612, 5,453,446, 5,457,133, 5,599,991, 5,744,500, 5,891,923, 5,668,181, 5,576,353, 5,519,061, 5,786,390, 6,316,504, 6,630,514 disclose R(+)-N-propargyl-1-aminoindan (“R-PAI”), also known as rasagiline. U.S. Pat. No. 6,126,968 and PCT International Application Publication No. WO 95/11016 disclose pharmaceutical compositions comprising rasagiline. Rasagiline has been reported to be a selective inhibitor of the B-form of the enzyme monoamine oxidase (“MAO-B”) and is useful in treating Parkinson's disease and various other conditions by inhibition of MAO-B in the brain.
A formulation of rasagiline mesylate is approved for treating Parkinson's disease either as monotherapy or as an adjunct with other treatments. See, e.g. AZILECT®, Physicians' Desk Reference 2009 (PRD, 63th Edition).
AZILECT® is indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease as initial monotherapy and as adjunct therapy to levodopa. Rasagiline, the active ingredient of AZILECT®, is rapidly absorbed, reaching peak plasma concentration (Cmax) in approximately 1 hour. The absolute bioavailability of rasagiline is about (AZILECT® Product Label, May 2006).
There are, however, several concerns associated with the commercially available form of rasagiline mesylate. For example, a concern with the use of monoamine oxidase (“MAO”) inhibitors is the risk of hypertensive crises, often called the “cheese effect.” (Simpson, G. M. and White K. “Tyramine studies and the safety of MAOI drugs.” J Clin Psychiatry. 1984 July; 45 (7 pt 2): 59-91.) Such an effect is caused by inhibition of peripheral MAO. A high concentration of peripheral MAO is found in the stomach.
Another concern in Parkinson's disease patients is that many patients suffer from delayed gastric emptying (Pfeiffer, R. F. and Quigley, E. M. M. “Gastrointestinal motility problems in patients with Parkinson's disease: Epidemiology, pathophysiology, and guidelines for management,” CNS-Drugs, 1999, 11(6): 435-448; Jost, W. H., “Gastrointestinal motility problems in patients with Parkinson's disease: Effects of antiparkinsonian treatment and guidelines for management”, Drugs and Aging, 1997, 10(4): 249-258). Delayed gastric emptying (prolonged gastric residence) can be a cause of increased inhibition of peripheral MAO, and can contribute to the cheese effect.
There is also a concern regarding the potential for formation of alkyl mesylates during the treatment of the free base of a drug substance with methane sulfonic acid if any residues of short-chain alcohols are present. (Snodin D., “Residues of genotoxic alkyl mesylates in mesylate salt drug substances: Real or imaginary problems?” Regulatory Toxicology and Pharmacology, Vol. 45, 2006, pages 79-90).
Efforts to address such concerns and to improve the commercially available form of rasagiline mesylate are described in the literature. For example, PCT International Application Publication No. WO 2006/057912 describes orally disintegrating rasagiline compositions; PCT International Application Publication No. WO 2006/014973 discloses delayed release rasagiline compositions; PCT International Application Publication No. WO 2008/076348 discloses a crystalline solid form of the rasagiline base; PCT International Application Publication No. WO 2008/076315 discloses the tannate salt of rasagiline. Other efforts to make certain improvements are described in PCT International Application Publication No. WO 2008/019871 and in PCT International Application Publication No. WO 2008/131961.
However, the previous efforts did not disclose the citrate salt of rasagiline or the advantages of the citrate salt of rasagiline, described herein.